Hypoxia is one of the major pathological factors affecting brain function. The aim of the present study was to describe the effect of neonatal hypobaric hypoxia on the behavior of rats and to analyze its effect on hippocampal neurodegeneration. Hypobaric hypoxia at a simulated altitude of 9000 m was induced for one hour in neonatal rat pups (PND7 and PND9) of both sexes. Subsequently, the rats underwent behavioral testing on PND25 and PND35 using a LABORAS apparatus to assess spontaneous behavior. Hypoxia did not cause any morphological damage in the hippocampus of rats. However, hypoxia on PND7 led to less horizontal locomotor activity both, in males (on PND25) and females (on PND35). Hypoxia on PND9 led to higher rearing in females on PND25. Hypoxic males exhibited higher grooming activity, while females lower grooming activity on PND35 following hypoxia induced on PND7. In females, hypoxia on PND9 resulted in higher grooming activity on PND25. Sex differences in the effect of hypoxia was observed on PND35, when hypoxic males compared to hypoxic females displayed more locomotor, rearing and grooming activity. Our data suggest that hypoxia on PND7 versus PND9 differentially affects locomotion and grooming later in adolescence and these effects are sex-dependent.

Institute of Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

Zobrazit více v PubMed

ARTENI NS, PEREIRA LO, RODRIGUES AL, LAVINSKY D, ACHAVAL ME, NETTO CA. Lateralized and sex-dependent behavioral and morphological effects of unilateral neonatal cerebral hypoxia-ischemia in the rat. Behav Brain Res. 2010;210:92–98. doi: 10.1016/j.bbr.2010.02.015. PubMed DOI

ARUMUGAM TV, BAIK SH, BALAGANAPATHY P, SOBEY CG, MATTSON MP, JO DG. Notch signaling and neuronal death in stroke. Prog Neurobiol. 2018;165–167:103–116. doi: 10.1016/j.pneurobio.2018.03.002. PubMed DOI PMC

BERGER R, GARNIER Y, JENSEN A. Perinatal brain damage: underlying mechanisms and neuroprotective strategies. J Soc Gynecol Investig. 2002;9:319–328. doi: 10.1177/107155760200900601. PubMed DOI

BISWAL S, SHARMA D, KUMAR K, NAG TC, BARHWAL K, HOTA SK, KUMAR B. Global hypoxia induced impairment in learning and spatial memory is associated with precocious hippocampal aging. Neurobiol Learn Mem. 2016;133:157–170. doi: 10.1016/j.nlm.2016.05.011. PubMed DOI

BOGDANOVA OV, ABDULLAH O, KANEKAR S, BOGDANOV VB, PRESCOT AP, RENSHAW PF. Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia. Behav Brain Res. 2014;263:203–209. doi: 10.1016/j.bbr.2014.01.027. PubMed DOI PMC

BONA E, HAGBERG H, LOBERG EM, BAGENHOLM R, THORESEN M. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr Res. 1998;43:738–745. doi: 10.1203/00006450-199806000-00005. PubMed DOI

CARTY ML, WIXEY JA, KESBY J, REINEBRANT HE, COLDITZ PB, GOBE G, BULLER KM. Long-term losses of amygdala corticotropin-releasing factor neurons are associated with behavioural outcomes following neonatal hypoxia-ischemia. Behav Brain Res. 2010;208:609–618. doi: 10.1016/j.bbr.2010.01.007. PubMed DOI

CHEN PZ, HE WJ, ZHU ZR, EGJ, XU G, CHEN DW, GAO YQ. Adenosine A2A receptor involves in neuroinflammation-mediated cognitive decline through activating microglia under acute hypobaric hypoxia. Behav Brain Res. 2018;347:99–107. doi: 10.1016/j.bbr.2018.02.038. PubMed DOI

CLANCY B, DARLINGTON RB, FINLAY BL. Translating developmental time across mammalian species. Neuroscience. 2001;105:7–17. doi: 10.1016/S0306-4522(01)00171-3. PubMed DOI

COSTELOE K, HENNESSY E, GIBSON AT, MARLOW N, WILKINSON AR. The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics. 2000;106:659–671. doi: 10.1542/peds.106.4.659. PubMed DOI

CUAYCONG M, ENGEL M, WEINSTEIN SL, SALMON E, PERLMAN JM, SUNDERAM S, VANNUCCI SJ. A novel approach to the study of hypoxia-ischemia-induced clinical and subclinical seizures in the neonatal rat. Dev Neurosci. 2011;33:241–250. doi: 10.1159/000331646. PubMed DOI PMC

DOBLE A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. 1999;81:163–221. doi: 10.1016/S0163-7258(98)00042-4. PubMed DOI

DONDERS J, HOFFMAN NM. Gender differences in learning and memory after pediatric traumatic brain injury. Neuropsychology. 2002;16:491–499. doi: 10.1037//0894-4105.16.4.491. PubMed DOI

ESTANISLAU C, DIAZ-MORAN S, CANETE T, BLAZQUEZ G, TOBENA A, FERNANDEZ-TERUEL A. Context-dependent differences in grooming behavior among the NIH heterogeneous stock and the Roman high- and low-avoidance rats. Neurosci Res. 2013;77:187–201. doi: 10.1016/j.neures.2013.09.012. PubMed DOI

ESTANISLAU C, VELOSO AWN, FILGUEIRAS GB, MAIO TP, DAL-COL MLC, CUNHA DC, KLEIN R, CARMONA LF, FERNANDEZ-TERUEL A. Rat self-grooming and its relationships with anxiety, dearousal and perseveration: Evidence for a self-grooming trait. Physiol Behav. 2019;209:112585. doi: 10.1016/j.physbeh.2019.112585. PubMed DOI

GINET V, SPIEHLMANN A, RUMMEL C, RUDINSKIY N, GRISHCHUK Y, LUTHI-CARTER R, CLARKE PG, TRUTTMANN AC, PUYAL J. Involvement of autophagy in hypoxic-excitotoxic neuronal death. Autophagy. 2014;10:846–860. doi: 10.4161/auto.28264. PubMed DOI PMC

HILL CA, ALEXANDER ML, McCULLOUGH LD, FITCH RH. Inhibition of X-linked inhibitor of apoptosis with embelin differentially affects male versus female behavioral outcome following neonatal hypoxia-ischemia in rats. Dev Neurosci. 2011;33:494–504. doi: 10.1159/000331651. PubMed DOI PMC

HILL CA, FITCH RH. Sex differences in mechanisms and outcome of neonatal hypoxia-ischemia in rodent models: implications for sex-specific neuroprotection in clinical neonatal practice. Neurol Res Int. 2012;2012:867531. doi: 10.1155/2012/867531. PubMed DOI PMC

HUANG HZ, WEN XH, LIU H. Sex differences in brain MRI abnormalities and neurodevelopmental outcomes in a rat model of neonatal hypoxia-ischemia. Int J Neurosci. 2016;126:647–657. doi: 10.3109/00207454.2015.1047016. PubMed DOI

JAYALAKSHMI K, SINGH SB, KALPANA B, SAIRAM M, MUTHURAJU S, ILAVAZHAGAN G. N-acetyl cysteine supplementation prevents impairment of spatial working memory functions in rats following exposure to hypobaric hypoxia. Physiol Behav. 2007;92:643–650. doi: 10.1016/j.physbeh.2007.05.051. PubMed DOI

LAN WC, PRIESTLEY M, MAYORAL SR, TIAN L, SHAMLOO M, PENN AA. Sex-specific cognitive deficits and regional brain volume loss in mice exposed to chronic, sublethal hypoxia. Pediatr Res. 2011;70:15–20. doi: 10.1203/PDR.0b013e31821b98a3. PubMed DOI PMC

LAUTERBACH MD, RAZ S, SANDER CJ. Neonatal hypoxic risk in preterm birth infants: the influence of sex and severity of respiratory distress on cognitive recovery. Neuropsychology. 2001;15:411–420. doi: 10.1037//0894-4105.15.3.411. PubMed DOI

MAYORAL SR, OMAR G, PENN AA. Sex differences in a hypoxia model of preterm brain damage. Pediatr Res. 2009;66:248–253. doi: 10.1203/PDR.0b013e3181b1bc34. PubMed DOI PMC

NEHLIG A, PEREIRA De VASCONCELOS A. Glucose and ketone body utilization by the brain of neonatal rats. Prog Neurobiol. 1993;40:163–221. doi: 10.1016/0301-0082(93)90022-K. PubMed DOI

NETTO CA, SANCHES E, ODORCYK FK, DURAN-CARABALI LE, WEIS SN. Sex-dependent consequences of neonatal brain hypoxia-ischemia in the rat. J Neurosci Res. 2017;95:409–421. doi: 10.1002/jnr.23828. PubMed DOI

NYAKAS C, BUWALDA B, LUITEN PG. Hypoxia and brain development. Prog Neurobiol. 1996;49:1–51. doi: 10.1016/0301-0082(96)00007-X. PubMed DOI

PAPPAS A, SHANKARAN S, McDONALD SA, VOHR BR, HINTZ SR, EHRENKRANZ RA, TYSON JE, YOLTON K, DAS A, BARA R, HAMMOND J, HIGGINS RD. Cognitive outcomes after neonatal encephalopathy. Pediatrics. 2015;135:e624–e634. doi: 10.1542/peds.2014-1566. PubMed DOI PMC

PETERSON BL, WON S, GEDDES RI, SAYEED I, STEIN DG. Sex-related differences in effects of progesterone following neonatal hypoxic brain injury. Behav Brain Res. 2015;286:152–165. doi: 10.1016/j.bbr.2015.03.005. PubMed DOI

POTTER M, ROSENKRANTZ T, FITCH RH. Behavioral and neuroanatomical outcomes in a rat model of preterm hypoxic-ischemic brain injury: Effects of caffeine and hypothermia. Int J Dev Neurosci. 2018;70:46–55. doi: 10.1016/j.ijdevneu.2018.02.001. PubMed DOI

RAZ S, LAUTERBACH MD, HOPKINS TL, GLOGOWSKI BK, PORTER CL, RIGGS WW, SANDER CJ. A female advantage in cognitive recovery from early cerebral insult. Dev Psychol. 1995;31:958. doi: 10.1037/0012-1649.31.6.958. DOI

RILJAK V, KRAF J, DARYANANI A, JIRUSKA P, OTAHAL J. Pathophysiology of perinatal hypoxic-ischemic encephalopathy - biomarkers, animal models and treatment perspectives. Physiol Res. 2016;65:S533–S545. PubMed

RILJAK V, MARESOVA D, POKORNY J. Nicotine effects on rat seizures susceptibility and hippocampal neuronal degeneration. Neuro Endocrinol Lett. 2010;31:792–795. PubMed

RILJAK V, MILOTOVA M, JANDOVA K, POKORNY J, LANGMEIER M. Morphological changes in the hippocampus following nicotine and kainic acid administration. Physiol Res. 2007;56:641–649. PubMed

ROMIJN HJ, HOFMAN MA, GRAMSBERGEN A. At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? Early Hum Dev. 1991;26:61–67. doi: 10.1016/0378-3782(91)90044-4. PubMed DOI

SANCHES EF, ARTENI N, NICOLA F, ARISTIMUNHA D, NETTO CA. Sexual dimorphism and brain lateralization impact behavioral and histological outcomes following hypoxia-ischemia in P3 and P7 rats. Neuroscience. 2015;290:581–593. doi: 10.1016/j.neuroscience.2014.12.074. PubMed DOI

SARNAT HB, SARNAT MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33:696–705. doi: 10.1001/archneur.1976.00500100030012. PubMed DOI

SEMPLE BD, BLOMGREN K, GIMLIN K, FERRIERO DM, NOBLE-HAEUSSLEIN LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013;106–107:1–16. doi: 10.1016/j.pneurobio.2013.04.001. PubMed DOI PMC

SHEN Y, LIU XB, PLEASURE DE, DENG W. Axon-glia synapses are highly vulnerable to white matter injury in the developing brain. J Neurosci Res. 2012;90:105–121. doi: 10.1002/jnr.22722. PubMed DOI PMC

TOWFIGHI J, MAUGER D, VANNUCCI RC, VANNUCCI SJ. Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia-ischemia: a light microscopic study. Brain Res Dev Brain Res. 1997;100:149–160. doi: 10.1016/S0165-3806(97)00036-9. PubMed DOI

Van de WEERD HA, BULTHUIS RJ, BERGMAN AF, SCHLINGMANN F, TOLBOOM J, Van LOO PL, REMIE R, BAUMANS V, Van ZUTPHEN LF. Validation of a new system for the automatic registration of behaviour in mice and rats. Behav Processes. 2001;53:11–20. doi: 10.1016/S0376-6357(00)00135-2. PubMed DOI

VANNUCCI RC. Experimental biology of cerebral hypoxia-ischemia: relation to perinatal brain damage. Pediatr Res. 1990;27:317–326. doi: 10.1203/00006450-199004000-00001. PubMed DOI

VIRUES-ORTEGA J, BUELA-CASAL G, GARRIDO E, ALCAZAR B. Neuropsychological functioning associated with high-altitude exposure. Neuropsychol Rev. 2004;14:197–224. doi: 10.1007/s11065-004-8159-4. PubMed DOI

VOLPE JJ. Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev. 2001;7:56–64. doi: 10.1002/1098-2779(200102)7:1<56::AID-MRDD1008>3.0.CO;2-A. PubMed DOI

ZAYACHKIVSKY A, LEHMKUHLE MJ, EKSTRAND JJ, DUDEK FE. Ischemic injury suppresses hypoxia-induced electrographic seizures and the background EEG in a rat model of perinatal hypoxic-ischemic encephalopathy. J Neurophysiol. 2015;114:2753–2763. doi: 10.1152/jn.00796.2014. PubMed DOI PMC

ZHANG XY, ZHANG XJ, XV J, JIA W, PU XY, WANG HY, LIANG H, ZHUOMA L, LU DX. Crocin attenuates acute hypobaric hypoxia-induced cognitive deficits of rats. Eur J Pharmacol. 2018;818:300–305. doi: 10.1016/j.ejphar.2017.10.042. PubMed DOI

ZHU C, WANG X, XU F, BAHR BA, SHIBATA M, UCHIYAMA Y, HAGBERG H, BLOMGREN K. The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia. Cell Death Differ. 2005;12:162–176. doi: 10.1038/sj.cdd.4401545. PubMed DOI

ZHURAVIN IA, DUBROVSKAYA NM, VASILEV DS, POSTNIKOVA TY, ZAITSEV AV. Prenatal hypoxia produces memory deficits associated with impairment of long-term synaptic plasticity in young rats. Neurobiol Learn Mem. 2019;164:107066. doi: 10.1016/j.nlm.2019.107066. PubMed DOI

The GluN2B-Containing NMDA Receptor Alleviates Neuronal Apoptosis in Neonatal Hypoxic-Ischemic Encephalopathy by Activating PI3K-Akt-CREB Signaling Pathwa

Sex Difference in Plasma Deoxyribonuclease Activity in Rats

The critical role of hippocampal dopamine in the pathogenesis of hepatic encephalopathy

Neonatal hypoxic-ischemic brain injury leads to sex-specific deficits in rearing and climbing in adult mice

Perinatal hypoxic-ischemic damage: review of the current treatment possibilities